Definition

A IUPAC task group is in charge of defining the halogen bond and their provisional definition is the following:ⁱ “A halogen bond R-XY-Z occurs when there is evidence of a net attractive interaction between an electrophilic region on a halogen atom X belonging to a molecule or a molecular fragment R-X (where R can be another atom, including X, or a group of atoms) and a nucleophilic region of a molecule, or molecular fragment, Y-Z”

iRecommendation submitted by the IUPAC task group (2009-032-1-100)

X Y

^R

R' ^R'

X Y

^R

X: I, Br, Cl, F Y: N, O, S, Cl^-,Br^- ,I^- ,F^-, etc.

Figure 32: Scheme of a simple definition of halogen bonds.

A less formal definition would define the halogen bond as the attractive interaction between the electropositive region of a halogen atom and a Lewis base, this situation is described in Figure 32. However, such a definition excludes many possibilities and considers mainly the electrostatic component of the halogen bond; other contributions are to be considered as well.^115,116 1.5.2 Characteristics

The strength of the halogen bonding interaction ranges from 5 to 180 kJ mol^{−1 117} with the higher limit being the rather particular case of iodide with iodine interaction in the formation of polyiodides^118,119In fact, several studies, theoretical and experimental, have aimed at the comparison of the strength of halogen bonds against hydrogen bonds, with the general conclusion that they have comparable strengths, but this depends strongly on the cases.

The usual way halogen bonds are identified is in crystal structures, where a short contact of less than the sum of the van der Waals radii, is observed.

One important characteristic of the halogen bond is the fact that its halogen-bond donor moieties, which are usually simple halocarbons, are not intrinsi-cally hydrophilic, which is the case in hydrogen-bond donors. This difference has implications in most of the applications ranging from anion receptors to medicinal chemistry.¹²⁰

1.5.3 Theσ-Hole

The main contribution to the formation of a halogen bond is the electrostatic one. This contribution allows for the description of the bonding event in terms of itsσ-hole.

1 Introduction 39

The term σ-hole was proposed by Politzer¹²¹ and is described as being mainly the consequence of the formation of the C-X bond that generates a situation where the three unshared electron pairs can be described as as²p_x²p²_y where s has decreasing levels of sp hybridization when passing from F (ca.

25%) to I (ca. 8.4%). Another more intuitive way to describe theσ-hole is based on the polarizability of the halogen atom which increases when passing from F to I. In the case of a C-X bond formation, the electronic density is used for the bonding event and thus decreases in the halogen itself leading to the formation of a positive region which is theσ-hole.

In both cases, the formation of this positive region occurs directly opposite to the C-X bond, and increases in size and charge with increasing polariz-ability. Figure 33 shows the evolution of the σ-hole when changing from tetrafluoromethane to trifluoroiodomethane.¹¹³

R δ+

δ-X ^Lewis_base Lewis

acid

180°

90°

Figure 33: Molecular electrostatic potential for CF4, CF3Cl, CF3Br, CF3I as de-scribed by Metrangolo¹¹³ (left) and schematic representation of a halo-gen bond donor with positive and negative regions (right).

Halogen atoms are usually considered to be good nucleophiles and Lewis bases; the fact that the p_z orbital is depleted and presents a σ-hole does not affect the whole halogen atom. Indeed, a belt of negative charge exists per-pendicularly to the z axis (C-X axis) and can engage in non-covalent bonding as well and even simultaneously.¹²²

1.5.4 About Halogen Bonding Strength

The strength of the halogen bonding interaction deserves a special comment.

Most halogen bonds that are reported in the literature to this date involve fluorinated materials. It has been suggested recently that perfluorination in iodo-arene compounds only accounts for a 50% gain in binding energies in a typical protein-ligand situation.¹²⁰

This is partially supported by theoretical studies by Huber¹¹⁵and Politzer¹²³ Politzer reported a systematic study in which the interaction energies for several aceto-halo-arenes were followed with an increasing number of fluoro substituents on the arene, this at the MP2 aug-cc-pVDZ-PP level of theory.

Interestingly, an increase of 85% in the binding energy of iodoperfluorobenzene as compared to iodobenzene was reported.¹²³

The Huber group studied the effect of perhalogenation in halomethane and its interaction with chloride and trimethylamine. It was reported that the use of perfluorinated material shows a weaker performance as compared to perhalogenation with higher halogens. The conclusion of their studies was that although theσ-hole is an excellent description of the halogen-bond donor character of a molecule, the binding itself is better helped by more polarizable units due to the non-negligible quantum chemical contributions of charge transfer and Pauli repulsion.¹¹⁵

Overall, halogen bonds are highly tunable interactions that are not to be limited in their application to perfluorinated materials; in most cases the use of alternative halogen-bond donor moieties could be helpful.

1.5.5 Geometry of Halogen Bonds

One very important feature of halogen bonds is the directionality. As a con-sequence of what is shown in Figure 33, the non-covalent bond formed by the interaction of the halogen-bond donor and a Lewis base is forced to take place at 180^◦ to the C-X bond. This bonding event will be much more affected by an offset shift than its homologous hydrogen bond.^124–126 This holds true as well to the site interactions at 90^◦, which are severely affected by an offset displacement.

1 Introduction 41

This characteristic, in addition to the distance difference that exists con-comitantly to the use of a halogen instead of a hydrogen, accounts for the geometrical differences of halogen bonds.

1.5.6 Halogen Bonding in Crystal Engineering

This has been the main field of research concerned with halogen bonding over the last twenty years. In this context, halogen bonds have been used together with typical hydrogen-bonding acceptor like amines and halides. As this field enjoys its own complexity, the reader is rather directed to specialized reviews on the matter.^108,113

It is worth mentioning that most of the research in crystal engineering exploits perfluorinated halogen-bond donors, due to their strength and rigid-ity, and both alkanes and arenes have been used. In a typical example, α-methylbenzylammonium chloroacetate would crystalize spontaneously to form infinite chains, or the (4,4) networks formed upon co-crystalization of 1,4-difluoro-2,3,5,6-tetraiodobenzene with bromide (Figure 34).¹⁰⁸

In general, halogen bonding contributes to different geometrical constraints but the normal rules as to nodes and networks still apply unchanged.

1.5.7 Halogen Bonding in Anion Binding

Examples in this field are scarce but significant. The first example reported was from the Metrangolo and Resnati groups in Milan¹⁰⁹and marked the starting point for the application of halogen bonding in solution; in the meantime other better examples have appeared that will be discussed in the following.

The first pure halogen bonding anion receptor was achieved by the Taylor group with the tripodal receptor80(Figure 35). This receptor and the required controls, like the pure perfluorinated analogue and the two- (81) and one-armed analogues, were tested for anion binding in acetone. The association constants were determined by¹⁹F NMR titrations with tetrabutylammonium (TBA) salts.

The tripodal receptor80shows the best association constants with Ka: ca.

2·10⁴M⁻¹for the80·Cl⁻complex. The binding affinity decreases in the series

A

B

C

D

E

Figure 34: Crystal structure formed by crystalization of (A) α-methylbenzylammonium chloroacetate, (B) 1,10-diazonia-18-crown-6 bis(trichloroacetate), (C) ammonium 2-amino-3,5-dichlorobenzoate;

co-crystalization of (D) bromide anions with 1,4-difluoro-2,3,5,6-tetraiodobenzene, (E) chloride anions with diiodoacetylene. Color code:

grey, carbon; blue, nitrogen; light brown, bromine; red, oxygen; green, chlorine; yellow, sulfur; violet, iodine; yellowgreen, fluorine. Cations and hydrogen atoms are omitted.¹⁰⁸

1 Introduction 43

Figure 35:Anion receptors proposed by the Taylor group.^127,128

Cl⁻, Br⁻ and I⁻ as predicted by the theory. The study was complemented with computational calculations to confirm the feasibility and the geometry of the design.¹²⁷

Later, in a separate report, receptor82was introduced, which combines the binding properties of urea derivatives with those of two halogen-bond donors.

This system was designed to explore the contribution of halogen bonding to this kind of receptors analogously to what the Ballester group did with anion-π interactions.¹⁰¹

The use of this “mixed” system entails to deal with several controls including the anion-πcontrol. At the end of a careful study, supported by computational modeling, binding affinities as high as K_a: 2.4·10³M⁻¹ were obtained for the complex 82·Cl⁻. Although this binding affinity is smaller than the one reported for 80, it was possible, under these conditions, to calculate the net halogen-bonding contribution that was in the order of 2 kcal mol⁻¹.¹²⁸

For bromide and iodide the trend observed before was maintained but, in addition, this new receptor was able to bind oxoanions like benzoate proving that the simultaneous use of halogen bonds and hydrogen bonds is possible.

N N

Figure 36:Anion receptors proposed by the Beer group.^129,130

Another series of interesting receptors was reported by the Beer group.^129,130 In their examples, the halo-imidazolium moiety was used as halogen-bond donor in bidentate halo-imidazoliaphane receptors (Figure 36). This approach has two important advantages: on the one hand, the use of charge-assisted halogen bonding gives better binding and, on the other hand, it allows for a high water solubility.

In the first example, receptor83 shows a main difference to the hydrogen bond control 84: 83 presents fixed syn andanti configurations, whereas 84 can freely interchange them. Under these conditions, NMR titrations permit the measurement of association constants as high as 889 M⁻¹ for bromide in an ACN/water 9:1 mixture. Interestingly, other anions gave significantly weaker associations (<10 M⁻¹ for chloride and 184 M⁻¹for iodide) and the hydrogen bonding version84gave constant, non-selective associations in the range of∼100 M⁻¹.

This selectivity has its origin in the different steric constraints of halogen-bond and hydrogen-halogen-bond donors. Indeed, it leads to the preorganization in thesynconformation of83while this is not possible with84. Additionally, for the same reason, a “bidentate” binding is only possible with the bigger anions for the halogen bonding case, whereas it is always possible with the hydrogen bonding one.

1 Introduction 45

This concept was expanded with the anion receptors85to88; in this case the phenyl spacers were replaced by naphthalenes adding, in consequence, a fluorescence read-out. The much bigger spacer would allow for a much higher freedom and only the iodo derivative88would be fixed insynandanti conformations.

The anion bindings were determined by fluorescence titrations and revealed a markedly stronger binding with compounds87 and88as compared to the other potential receptors. Interestingly, binding happens preferentially with bromide and iodide with more than one order of magnitude difference in the association constants; moreover, where receptor 87 binds bromide preferen-tially (twenty times stronger),88rather bind iodide (thirty times better), with association constants as high as 10⁶ in ACN/water 9:1 These receptors rep-resent the best receptors in aqueous phase that use halogen bonding. This work was supported with the corresponding solid state and modeling data.

More importantly, these receptors are extraordinary examples of the pe-culiarities of halogen-bond donors as compared to their hydrogen-bond ana-logues, namely, the steric constraints of using big halogens and the quicker loss in binding strength when moving from the ideal 180^◦ binding angle.

1.5.8 Halogen Bonding in Catalysis

Halogen bonding has already been used in catalysis in some pioneering work by the Bolm¹³¹and Huber¹³² groups.

The first example of catalysis with halogen bonds came from the Bolm group in 2008.¹³¹ The use of haloperfluoroalkanes like 89 to catalyze the hydrogenation of quinolines was proposed.

Quinoline90 is not reduced by the Hantzsch ester (107) in DCM at room temperature. The presence of a haloperfluoroalkane like 89 activates this hydrogenation reaction by halogen-bond formation between the quinoline ni-trogen and compound89; the reaction can then proceed naturally to product 92. Yields as high as 90% were reported with this system.

The scope of the reaction was tested and it was shown that quinolines93 to99can be reduced in the presence of haloperfluoroalkanes to the respective compounds 100to106in yields ranging from 70% to 98%.¹³¹

N

Scheme 2:Halogen-bond activation of the hydrogenation of quinolines proposed by the Bolm group.¹³¹

Br HN

Scheme 3:Halogen-bond activation of a Ritter-like reaction proposed by the Huber group.^132–134

1 Introduction 47

The Huber group proposed the use of halogen-bond donors as Lewis acids to activate the Ritter-like reaction of benzhydryl bromide 108in acetonitrile to give the corresponding amide109(Scheme 3). Under these conditions, the stronger the bond formed with the bromide the faster was the reaction.

Three different charge-assisted halogen-bond donors were used: iodoimida-zolium¹³² (110) , iodo-pyridinium¹³³ (111), or iodo-triazolium¹³⁴ (112) in multi-valent scaffolds. The structures presented here are the ones showing the best performance; many variations were tried. The results demostrate the possibility of using halogen bonds as Lewis acid catalysts.

The binding of the family of catalyst 110 was further investigated, and assotiation constants as high as 10⁵ M⁻¹ in acetonitrile and 10⁶ M⁻¹ in chloroform with bromide were obtained.¹³⁵This confirms the strength of the complex formation.

Halogen-bond donors have been used as well to promote the ring opening polymerization of (L)-lactide;¹³⁶ here again the halogen-bond donor is only used as a Lewis acid.

1.5.9 Halogen Bonding in Medicinal Chemistry

The possibility of using halogen bonding in drug discovery and medicinal chem-istry has attracted attention in recent years.^137,138 The main reason for this renewed interest lies in the re-discovery that many commercial drugs include halogen atoms, included mainly during the optimization processes, and that short contacts exist between these halogens and, for instance, the host pro-tein. This shows that the role of the halogen atoms goes beyond the original design and thus its new potential is most intriguing.

Although not many examples of a successful use of halogen bonds in drug design exist, in recent years a number of detailed surveys of the Cambridge Crystal Database have shown that the serendipitous presence of halogen bonds in drug-protein crystals is, in fact, important.^120,122

One excellent example of the use of halogen bonds in drug discovery was reported by the Boeckler group,¹³⁹while dealing with the Y220C mutant of the p53 protein. The Y220C mutant is inactivated by a mutation destabilizing the tertiary structure of the protein and leading subsequently to the inactivation

I

114 115 116 117

Figure 37: Small molecules used by the Boeckler group to reactivate the Y220C mutant of the p53 protein.^132–134

of its function. Drugs could be used to stabilize the protein. A new halogen-enriched fragment library was employed to screen for potential candidates.

Compound 113was a leading fragment in the binding screening. Finally, compounds 114to117(Figure 37) were some of the compounds studied in detail by the means of solid-state crystal structure, isothermal calorimetry and differential scanning fluorimetry to assess the binding affinities and especially to obtain the gains in thermal stability of the Y220C mutant. Compound117 leads to a significant gain in stability and thus proved that the use of halogen bonding is a promising approach in drug discovery.

More classical examples can be found as well: the Diederich group reported an inhibitor of human Cathepsin L (hCatL) that was enriched with halogen substituents during the lead optimization process, giving a clear example of halogen-bond enhanced activity with a ten-fold increase for the halogenated drug as shown byin vitrostudies and solid-state crystal structures.¹⁴⁰

In both situations, short contacts of less than the sum of the van der Waals radius were observed, confirming the presence of functional halogen bonds.

1.5.10 Anion-π Interaction Enhanced by Halogen Bonding

It has been proposed by computational studies that anion-πinteraction could be enhanced by the use of halogen bonding coordination.¹⁴¹ This would be similar to the enhancement reported for compound64 with silver.⁹⁸

1 Introduction 49

This is only one of the many possibilities that remain to be explored in the field of halogen bonds and anion-π interactions suggesting that the field is open to future innovations.

surprising how often the circumstances fit in with them.

Sir William Osler

2 Objectives

The main goal of this work is to explore the usefulness of under-recognized non-covalent interactions when applied to anion transport systems. Two main non-covalent interactions will be covered: anion-π interactions and halogen bonds.

In the case of anion-πinteractions, results previously presented in the liter-ature with π-acidic NDIs will be extended to include sulfur-containing NDIs.

These newcomers with up to four sulfone substituents in the core should be extremely π-acidic and, as a consequence, their ability to transport anions through a lipid bilayer membrane is expected to be outstanding. In addition, a good anion transport activity would support the hypothesis that NDIs can be applied to anion transport regardless of the substitution, provided a favorable condition of π-acidity.

The role of self-assembly in the anion transport mechanism will be investi-gated with a more rigid structure by the introduction of o-tert-butyl groups on the NDIs diimide phenyl rings. This will give access to NDIs with axial chirality that will provide control over theπ-surface hindrance. Their observed activities as well as the Hill coefficients will allow us to better understand the underlying transport mechanism.

The idea of using anion-π interactions will then be applied to multiva-lent systems by decoration of calix[4]arenes and calix[4]pyrroles withπ-acidic phenyl rings. The success of this approach will establish anion-πinteractions as a relevant non-covalent interaction in the field of ion transport. Moreover, by using multivalent systems, strong preferences towards anion exchange should be observed; the conformational flexibility of the chosen scaffolds will allow us to elucidate these preferences.

Halogen bonding will be the main focus of this work. Initially, we will exploit the same calix[4]arene scaffold as used for the investigation of anion-π interactions. To do this, the π-acidic units will be replaced with halogen-bond donors; modulation of their strength should allow us to observe anion

2 Objectives 51

transport.

A minimalistic system will be explored later: the use of halogen-bond donors without any rigid scaffold will demonstrate that they are able to self-assemble into protective lipophilic shells that employ halogen bonds to transport an-ions. The use of several different halogen-bond donors will help us to better understand the system. A careful investigation of this system will be carried out to obtain a clean characterization. Ultimately, the use of planar bilayer conductance experiments will provide the best evidence that halogen bonds have properties, such as improved lipophilicity, that make them ideal for anion transport.

The last part of this work will be devoted to accessing better transport activities. To achieve this, a well studied system, the octiphenyl rigid-rod scaffold, will be modified. Decoration of this rigid rod with halogen-bond donors will give access to a membrane spanning rod, along which anions can slide by a hopping mechanism and thus rapidly move from one side of the membrane to the other. To confirm this hopping mechanism, oligophenyls of different lengths will be prepared and tested for anion transport. A comparison of the obtained activities should verify the validity of our approach.

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